title: Differential pharmacologies of mecamylamine enantiomers: positive allosteric modulation and noncompetitive inhibition.
abstract: (+/-)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers of this drug show different profiles for inhibition of the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human alpha4beta2 NNR subtype expressed in subclonal human epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [S-(+)-mecamylamine] was more effective than TC-5213 [R-(-)-mecamylamine] in inhibiting the LS alpha4beta2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS alpha4beta2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS alpha4beta2 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, whereas it is more effective in suppressing LS receptor function. This feature could be relevant to therapeutic applications where such a selective mechanism of action is required.
authors.affiliation: Preclinical Research, Targacept, Inc., Winston-Salem, NC 27101, USA.
authors.forename: Nikolai B
authors.initials: NB
authors.lastname: Fedorov
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Benson
authors.forename: John
authors.initials: J
authors.lastname: Graef
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lippiello
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects* / Q000502:physiology; D055592:Biophysical Phenomena / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells; D006801:Humans; D008464:Mecamylamine / Q000737:chemistry / Q000494:pharmacology*; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D008464:Mecamylamine